Many types of electronic cigarettes (ECs) are currently in use, but the default flow rate used to simulate puffing is centered on tobacco cigarette flow rates. CORESTA offers several methods and technical guides for evaluation of ECs but there are few puffing topography studies focusing on sub-ohm ECs; differences between real-world usage and that found in the literature appear large. This study focuses on how power and flow rate affect the nicotine yield of a sub-ohm EC. A puffing system (Puff3rd) has been designed and used to produce and collect EC aerosol. Nicotine yield was measured by GC–MS at three power levels and four flow rates. Data analysis was conducted in SAS using the MIXED procedure. Power, flow rate, and their interaction were all significant predictors of nicotine yield. Nicotine yield increased with both the vaping power and the puff flow rate with significant interaction of the two. Findings indicate that using the current CORESTA flow rate (1100 mL/min) to evaluate third-generation ECs underestimates nicotine yield and likely overestimates pyrolysis products. Real users are expected to have 2–3× the nicotine dose measured at 1100 mL/min, which could confound epidemiological studies seeking to link nicotine delivery to product satisfaction and acceptability.